Alzheimer's disease (AD) is a neurodegenerative disorder in the brain cortex, and progressive loss of neurons along with the progression of the disease eventually results in dementia. Major neuropathological findings are brain atrophy, senile plaques, neurofibrillary tangles and amyloid angiopathy. In both AD and normal brain aging, neuronal loss and abnormal deposition of Aβ, a major, essential constituent in senile plaques and cerebrovascular amyloid, appear in a topologically unique fashion, these lesions predominating in particular areas of the cerebral cortex, such as the hippocampus and enthorhinal cortex, which participate in memory and recognition. Mounting evidence suggests that missense mutations in and around Aβ are responsible for several types of familial AD and related disorders (Chartier-Harlin, M. -C. et al., 1991, Nature 353: 844-846; Haass, C. et al., 1995, Nature Med. 1: 1291-1296; Van Broeckhoven, C. et al., 1990, Science 248: 1120-1122). Two causative genes for another type of familial AD were identified as encoding presenilin 1 and 2, similar transmembrane proteins presumably expressed in the endoplasmic reticulum and/or Golgi complex (Sherrington, R. et al., 1995, Nature 375: 754-760; Levy-Lehad, E. et al., 1995, Science 269: 970-977). These proteins may participate in the modification and processing of newly synthesized proteins including β-amyloid precursor protein (APP). Of the Aβ peptides found in the brain, Aβ1-42 is highly amyloidogenic and an increase of this within neuronal cells may be directly associated with the pathophysiology of AD (Hardy, J., 1995, Trends. Neurosci. 20: 154-159; Beyreuther, K. and Masters, C. L., 1997, Nature 389: 677-678; Younkin, S. G., 1995, Ann. Neurol. 37: 287-288). Recently, distinctive neuronal sites for the intracellular production of Aβ have been identified as the endoplasmic reticulum for Aβ1-42 and the trans-Golgi network for Aβ1-40 (Hartmann, T. et al., 1997, Nature Med. 3: 1016-1020; Cook, D. G. et al., 1997, Nature Med. 3: 1021-1023). These findings strongly suggest that any impairment in the modification, processing or trafficking of APP and the Aβ peptides is essentially linked to the pathophysiology of AD. Although the causative genes and proteins have been identified in rare familial AD cases, the majority of AD cases (more than 95%) are sporadic, and the genes or proteins responsible for the disease process have yet to be identified. Whatever the primary pathogenesis of individual AD cases, progression of AD results in the accumulation and aggregation of Aβ in the brain, which eventually may induce neuronal death possibly through Ca2+ ion-channel formation, free radical generation by microglia and/or an apoptotic mechanism (Loo, D. T. et al., 1993, Proc. Natl. Acad. Sci. USA 90: 7951-7955; Arispe, N. et al., 1993, Proc. Natl. Acad. Sci. USA 90: 567-571).
The proteolytic process that generates Aβ species has yet to be clarified. Although candidate proteases that have α, β or γ-secretase activity have been identified from various species and organs, the majority of them were prepared by assays of their activities with synthetic substrates, and only a few of these candidate proteases have activity for the natural APP substrate. Induction of any of the identified genes responsible for familial AD in transgenic mice failed to show the neuropathological findings detected in human brain. Recent findings for monkey brain microinjected with fibrillary Aβ suggest that the neurotoxicity of Aβ in vivo is a pathological reaction of the aged brain, predominantly in the higher primates (Geula, C. et al., 1998, Nature Med. 4: 827-831). These findings suggest that Aβ and Aβ-bearing peptides are generated in a species- and tissue-specific manner, but the molecular mechanism is unclear.